Various evidence from studies on animals and in vitro studies indicate that the omega-3 fatty acids, and especially the long-chain polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present in fish and in oils derived therefrom inhibit carcinogenesis and show potential anti-tumour activity. In vitro studies with human tumorous lines have shown convincingly that the omega-3 PUFAs, principally DHA, reduce the growth of various types of tumorous cells, including breast, bowel, pancreas, and in chronic myeloid leukaemia and melanoma. Epidemiological data on the association between fish consumption, as a marker for the take-up of omega-3 fatty acids, and the risk of cancer are nevertheless rather less consistent. It has only proved possible to establish that the ingestion of DHA and EPA reduces the growth of tumours in rodents, including tumours of the mammary gland, the colon, the prostate, the liver and the pancreas.
Moreover, various studies have shown that the omega-3 PUFAs selectively inhibit the proliferation of tumorous cells, being less toxic towards normal cells. This different sensitivity to the omega-3 PUFAs cannot be explained simply by differences in the take-up of fatty acids. Various mechanisms have been proposed by which the omega-3 fatty acids might alter the carcinogenic process, notably the following: suppression of biosynthesis of eicosanoids deriving from arachidonic acid (ARA); alterations in the activity of transcription factors, regulation of gene expression and intracellular marking; alteration of oestrogen metabolism; alteration of the generation of free radicals and reactive oxygen species and modifications in membrane fluidity.
The ARA-derived eicosanoids have been associated with tumour development. Various mechanisms exist by which the omega-3 fatty acids can reduce the biosynthesis of ARA-derived eicosanoids. Firstly, the omega-3 fatty acids are taken into the phospholipids of the membrane, where they partially replace the omega-6 fatty acids. Secondly, the omega-3 PUFAs compete with the omega-6 PUFAs as substrates of the desaturases and elongases, the omega-3 PUFAs having greater affinity for said enzymes. Finally, the omega-3 fatty acids inhibit cycloxygenase-2 at transcriptional level and compete with the omega-6 fatty acids as substrates of the cycloxygenases in formation of the eicosanoids.
Furthermore, the omega-3 PUFAs and their metabolytes can exercise some of their anti-tumour effects by affecting the expression of various genes or the activities of the signal-transmission molecules involved in controlling growth, differentiation, cellular apoptosis, angiogenesis and metastasis. The most important are the activated receptor of peroxysomal proliferation, that of nuclear transcription factor KB, the ras oncogene, protein kinase C, co-enzyme-A-3-hydroxyl-3-methylglutaril reductase, cycloxygenase-2, lipoxygenases and the nitric oxide synthase. It has been shown that the treatment of colon carcinoma cells with DHA alters the characteristics of the cellular membrane and reduce its metastasic capacity.
The generation of free radicals and reactive oxygen species appears to be involved in the initiation of apoptosis and in natural defences against the transformed cells. Thus the inhibitory effects of the long-chain omega-3 PUFAs on the growth of tumour cells can be explained, at least partly, by the formation of oxidation products, which leads to growth of the cell being halted and to the onset of the apoptosis process. It has been suggested that the tumour cells have a deficit of anti-oxidant defence systems in comparison with the healthy cells and are thus more susceptible to oxidation damage. The PUFAs are the main intracellular substrates in lipid peroxidation, whether it be by causing damage to the cell membranes, altering cellular composition or the assembly of the cytoskeleton, altering the membrane transport systems or the activity of their enzymes, or inhibiting the reactions of the polymerase. It is therefore reasonable to consider the DHA-enriched cells of the tumour as being more susceptible to oxidative damage.
There is a certain amount of evidence that the omega-3 fatty acids have an effect on the cell cycle. In vitro treatment with DHA leads to a stoppage in the G1/S or G2/M phase during the cell cycle in tumorous cells of breast and melanoma. In vivo, the administration of fish oil rich in omega-3 to rats implanted with a breast tumorous line can prolong replication of the DNA of the tumorous cells thereby delaying progression through the synthesis phase.
Preclinical studies have nevertheless shown that the omega-3 PUFAs can increase the cytotoxicity of several anti-neoplasic agents and the anti-carcinogenic effects of radiotherapy. These effects are possibly mediated by incorporation of the fatty acids into the tumour cell membranes, thus altering physical and functional characteristics.
On the other hand, the therapeutic efficacy achieved depends on several factors, such as the bioavailability of the fatty acid, which is in turn related with the chemical structure of which it forms part, the type of omega-3 PUFA used (ALA, EPA or DHA) and the interaction availability between the PUFA and the target cell.
Data resulting from a study in which the bloavailability of three concentrated omega-3 PUFAs in the form of ethyl esters, free fatty acids and triglycerides were compared following oral administration showed that the re-esterified triglycerides presented greater bioavailability than the other two preparations.
It was also shown in a multi-organ model of carcinogenesis that in a monotherapy treatment DHA is the omega-3 PUFA that provides most effective anti-tumour protection, exceeding that of EPA. This result has also been confirmed in combined EPA+DHA anti-tumour treatments, where the presence of EPA has been observed to diminish the efficacy of the DHA.
Finally, the administration route is an important aspect on which the efficacy of the system depends. For example, intratumour administration is the preferred route for the treatment of gliomas. It is essential in this respect that the PUFAs be administered to the patients in such a way as to be easily taken up by the tumorous cells. For parenteral administration, for example, which is suitable for the treatment of hepatomas, it is essential to have a carrier system such as an emulsion with the additional objective of limiting bonding of the PUFAs to the serum albumin that suppresses their tumour cytotoxicity. In the case of oral administration, suitable for the treatment of lymphomas, following processing and intestinal absorption the PUFAs are transported to the target tissue incorporated into the kilomicrons in the form of triglycerides.